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A cytotoxic senescent memory CD4 T cell population is resistant to cytopathic effects of HIV infection 3520

Year: 2025
Type: article
Abstract: Description People with HIV (PWH) on antiretroviral therapy harbor an HIV reservoir. This reservoir resides in resting memory CD4 T cells and is responsible for virus rebound after treatment interruption. This reservoir persists for decades, and the theorized mechanisms for this persistence are cellular survival and proliferation of HIV-infected cells. However, because HIV is cytopathic we explored the mechanism for how infected cells could proliferate and survive. We explored this question by directly infecting primary resting CD4 T cells with a CCR5-tropic replication-competent GFP reporter virus. We measured GFP expression and T-cell markers by spectral cytometry. We performed RNAseq of sorted GFP+ cells and uninfected CD4 T cells for transcriptome analysis. We measured proliferation by labeling resting infected cells with violet CellTrace and then stimulating them for 10 days with anti-CD3/CD28 nanobeads. We detected resting GFP+ cells 3 to 4 days after infection in CD45RO+ cells. Stimulated HIV-infected cells had detectable GFP+ cells after 10 days of T-cell proliferation. These GFP+ cells were primarily in the non-divided population and not in the divided population. Transcriptome analysis showed that resting infected cells upregulated cell cycle arrest genes CDKN1A and CDKN1B. Infected cells also upregulated survival genes KIT and BCL2, and cytotoxic genes GZMA, GZMB, and PRF1. We conclude that HIV can directly infect and persist in resting cytotoxic senescent memory CD4 T cells. Funding Sources NIH/NIAID 1ZIAAI005034-22 and NIH/NIAID 1ZIAAI005014-22 Topic Categories Viral Immunology (VIR)
DOI: 10.1093/jimmun/vkaf283.1314
Language: English
Subfield: Virology
Open Access status: bronze
OpenAlex ID: W4416451445
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